DESCRIPTION The neu/erbB2 receptor is over-expressed in 30% of breast cancers. Like erbB2, MUC1, an integral membrane glycoprotein, is highly expressed in breast cancers. To elucidate the role of Muc1 in tumor progression and metastasis our laboratory crossed MMTV-c-neu transgenic mice (Guy et al., 1992) onto a Muc1 nuol background (Spicer et al., 1995). Immunohistochemistry and western analysis have shown that the c-neu tumors have an absence to very low Muc1 expression. This was surprising because Muc1 is usually expressed at high levels in mouse mammary tumors as well as most human mammary tumors. We hypothesize that erbB2 negatively regulates Muc1 expression in the c-neu tumors and that down-modulation of Muc1 expression gives the c-neu expressing neoplastic cells a selective advantage during tumor evolution. Specific aim I: To determine if the down-regulation of Muc1 occurs at the level of RNA or protein, will be studied by northern analysis, immunoblots, and immunohistochemistry. Specific aim II: To determine at what point during tumor development does this down-regulation occur, will be assessed by taking tumors at different stages of tumor progression and analyzing them with immunohistochemistry and in situ hybridization. Specific aim II: To explore the mechanism by which neu/erbB2 down- regulates Muc1. Studies examining the down-modulation of proteins during progression are crucial for the development of potential therapeutic strategies.